Unit for Lymphopoiesis, Department of Immunology, Pasteur Institute, Paris, France.
INSERM U1223, Paris, France.
Front Immunol. 2018 Jun 7;9:1252. doi: 10.3389/fimmu.2018.01252. eCollection 2018.
The Notch pathway is one of the canonical signaling pathways implicated in the development of various solid tumors. During carcinogenesis, the Notch pathway dysregulation induces tumor expression of Notch receptor ligands participating to escape the immune surveillance. The Notch pathway conditions both the development and the functional regulation of lymphoid subsets. Its importance on T cell subset polarization has been documented contrary to its action on innate lymphoid cells (ILC). We aim to analyze the effect of the Notch pathway on type 1 ILC polarization and functions after disruption of the RBPJk-dependent Notch signaling cascade. Indeed, type 1 ILC comprises conventional NK (cNK) cells and type 1 helper innate lymphoid cells (ILC1) that share Notch-related functional characteristics such as the IFNg secretion downstream of T-bet expression. cNK cells have strong antitumor properties. However, data are controversial concerning ILC1 functions during carcinogenesis with models showing antitumoral capacities and others reporting ILC1 inability to control tumor growth. Using various mouse models of Notch signaling pathway depletion, we analyze the effects of its absence on type 1 ILC differentiation and cytotoxic functions. We also provide clues into its role in the maintenance of immune homeostasis in tissues. We show that modulating the Notch pathway is not only acting on tumor-specific T cell activity but also on ILC immune subset functions. Hence, our study uncovers the intrinsic Notch signaling pathway in ILC1/cNK populations and their response in case of abnormal Notch ligand expression. This study help evaluating the possible side effects mediated by immune cells different from T cells, in case of multivalent forms of the Notch receptor ligand delta 1 treatments. In definitive, it should help determining the best novel combination of therapeutic strategies in case of solid tumors.
Notch 通路是参与多种实体瘤发生发展的经典信号通路之一。在癌变过程中，Notch 通路失调诱导肿瘤表达 Notch 受体配体，从而逃避免疫监视。Notch 通路调节淋巴样细胞亚群的发育和功能调控。尽管 Notch 通路对先天淋巴细胞（ILC）有作用，但已有文献证明其对 T 细胞亚群极化也很重要。我们旨在分析 Notch 通路在破坏 RBPJk 依赖性 Notch 信号级联后对 1 型固有淋巴样细胞（ILC1）极化和功能的影响。实际上，1 型 ILC 包括传统 NK（cNK）细胞和 1 型辅助性固有淋巴样细胞（ILC1），它们具有与 Notch 相关的功能特征，如 T-bet 表达下游的 IFNg 分泌。cNK 细胞具有强大的抗肿瘤特性。然而，关于 ILC1 在癌变过程中的功能存在争议，一些模型显示其具有抗肿瘤能力，而另一些模型则报告 ILC1 无法控制肿瘤生长。我们使用各种 Notch 信号通路耗竭的小鼠模型，分析其缺失对 1 型 ILC 分化和细胞毒性功能的影响。我们还提供了有关其在组织免疫稳态维持中的作用的线索。我们表明，调节 Notch 通路不仅作用于肿瘤特异性 T 细胞活性，还作用于 ILC 免疫亚群功能。因此，我们的研究揭示了 Notch 信号通路在 ILC1/cNK 群体中的内在作用及其在异常 Notch 配体表达情况下的反应。这项研究有助于评估在 Notch 受体配体 delta 1 多价形式治疗的情况下，除 T 细胞以外的免疫细胞介导的可能副作用。总之，它应该有助于确定实体瘤治疗策略的最佳新组合。
